Chronic and excessive ethanol intake decreases hepatic retinoic acid (RA) concentrations, which may play a critical role in ethanol-induced hyperproliferation in hepatocytes. The present study was conducted to determine whether RA supplementation in chronic ethanol-fed rats could restore hepatic RA concentrations to normal levels and modulate hepatocyte hyperproliferation. Male Sprague-Dawley rats were divided into four groups: control, ethanol-fed, ethanol-fed + 50 microg all-trans-RA/kg body wt and ethanol-fed + 100 microg all-trans-RA/kg body wt. Ethanol was given to rats at 6.2% (v/v) in a liquid diet to provide 36% of total caloric intake. Control animals received the same amount of liquid diet with isocaloric maltodextrin in place of ethanol. Results show that the ethanol treatment in rats for a month significantly increased the mean number of proliferating cell nuclear antigen (PCNA)-positive hepatocytes [4.96 +/- 1.36% (ethanol-fed) versus 0.29 +/- 0.08% (control), P < 0.05]. This increase was associated with the induction of hepatic c-Jun protein (6.5-fold increase) and cyclin D1 protein (3-fold increase) in ethanol-fed animals as compared with controls. Furthermore, activator protein 1 (AP-1) DNA-binding activity was significantly higher in hepatic nuclear extracts from ethanol-fed rats than those from controls. In contrast, RA supplementation in ethanol-fed rats raised hepatic RA concentration to normal levels and almost completely abolished the ethanol-enhanced c-Jun, cyclin D and AP-1 DNA-binding activities. Moreover, RA supplementation at both doses markedly suppressed the ethanol-induced PCNA-positive hepatocytes by approximately 80%. These results demonstrate that the restoration of hepatic RA concentrations by dietary RA supplementation suppresses ethanol-induced hepatocyte proliferation via inhibiting c-Jun overexpression, and suggest that RA may play a role in preventing or reversing certain types of ethanol-induced liver injury.

Background/Objectives: To investigate the association of antioxidant nutritional status with the risk of atopic dermatitis (AD) in young children in a case-control, population-based study. Subjects/Methods: Identified from preschools by using the Korean version of the International Study of Asthma and Allergies in Childhood (ISAAC). Final analysis included 180 AD (mean age 5.3 ± 0.9 years) and 242 non-AD (mean age 5.2 ± 1.0 years) children. Diet was assessed using a validated semi-quantitative food frequency questionnaire. Fasting blood samples were used for analyses of fat-soluble vitamins (retinol, a-tocopherol, and b-carotene) and vitamin C. . There was no relationship of AD risk with dietary and plasma vitamin C as well as nutrient supplement intake regardless of nutrient type. AD was predicted better by the intake measure than the corresponding blood biomarker regarding vitamin E and b-carotene. Conclusions: These findings suggest that higher antioxidant nutritional status reduces the risk of AD and that such risk-reduction effects depend on nutrient type.

Chronic ethanol intake may interfere with retinoid signal transduction by inhibiting retinoic acid synthesis and by enhancing activator protein-1 (AP-1) (c-Jun and c-Fos) expression, thereby contributing to malignant transformation. To determine the effect of ethanol on hepatic retinoid levels, retinoic acid receptors (RARs) and AP-1 (c-Jun and c-Fos) gene expression, chronic ethanol (36% of total calorie intake) pair-feeding was conducted on rats for a 1-month period. Retinoic acid, retinol, and retinyl ester concentrations in both liver and plasma were examined by using high-performance liquid chromatography (HPLC). Both retinoic acid receptor (␣, ␤, ␥) and AP-1 (c-Jun and c-Fos) expression in the rat liver were examined by using Western blot analysis. Treatment with high-dose ethanol led to a significant reduction of retinoic acid concentration in both the liver and the plasma (11-and 8.5-fold reduction, respectively), as compared with animals pair-fed an isocaloric control diet containing the same amount of vitamin A. Similar to the retinoic acid reductions, both retinol and retinyl palmitate levels in the livers of the alcohol-fed group decreased significantly, but in smaller fold reduction (6.5-and 2.6-fold reduction, respectively). Ethanol did not modulate the expression of RAR␣, -␤, and -␥ genes in the liver. However, chronic alcohol feeding enhanced AP-1 (c-Jun and c-Fos) expression by 7-to 8-fold, as compared with the control group. These data suggest that functional downregulation of RARs by inhibiting biosynthesis of retinoic acid and up-regulation of AP-1 gene expression may be important mechanisms for causing malignant transformation by ethanol. (HEPATOLOGY 1998;28:744-750.)

Lycopene has been shown to be beneficial in protecting against high-fat diet-induced fatty liver. The recent demonstration that lycopene can be converted by carotene 9',10'-oxygenase into a biologically active metabolite, ALA, led us to propose that the function of lycopene can be mediated by ALA. In the present study, male ob/ob mice were fed a liquid high-fat diet (60% energy from fat) with ALA supplementation (ALA group, 240 μg · kg body weight(-1) · d(-1)) or without ALA supplementation as the control (C group) for 16 wk. Steatosis, SIRT1 expression and activity, genes involved in lipid metabolism, and ALA concentrations in the livers of mice were examined. The results showed that ALA supplementation resulted in a significant accumulation of ALA in the liver and markedly decreased the steatosis in the ALA group without altering body and liver weights compared to the C group. The mRNA and protein levels of hepatic SIRT1 were higher in the ALA group compared to the C group. SIRT1 activity also was higher in the ALA group, as indicated by the lower levels of acetylated forkhead box class O1 protein levels. In addition, the mRNA level of acetyl CoA carboxylase 1 was significantly lower in the ALA group than in the C group. Because SIRT1 plays a key role in lipid homeostasis, the present study suggests that the lycopene metabolite, ALA, protects against the development of steatosis in ob/ob mice by upregulating SIRT1 gene expression and activity.